Project Summary Skin works as more than a physical barrier. It also functions as an organ mounting the immune responses against harmful stimulations and invading microorganisms of the environment. However, advanced wound dressings have been studied primarily for wound closure through mechanisms such as vascularization, epithelialization, contraction, infection control or their combinations. No dressings have been studied with two primary functions of promoting both wound closure and immune homeostasis. Our recent results (Nature Immunology 2016) have shown that CCR10 (+) innate lymphoid cells are important for cutaneous homeostatic regulation, suggesting that the CCL27/CCR10 axis is a promising target in manipulating immune cells for skin homeostasis. Thus, the objective of this project is to study a novel semi-synthetic biomaterial for controlled release of CCL27 and vascular endothelial growth factor (VEGF). CCL27 will be used to promote immune homeostasis and VEGF will be used to promote wound closure. To achieve this objective, this biomaterial will be functionalized with aptamers. The use of aptamers is promising to solve a challenging contradictory situation where high permeability is necessary for efficient transport of oxygen and drugs to the wound bed but it limits sustained drug release. The preliminary results have demonstrated that highly permeable materials functionalized with aptamers can release VEGF in a sustained manner for accelerated wound closure. Based on these compelling preliminary data, the proposed research is aimed at testing a novel hypothesis that aptamer-mediated release of VEGF and CCL27 will promote both wound closure and immune homeostasis to restore the key functions of the skin. Specific aims include 1) synthesis and characterization of the semi- synthetic wound dressing; 2) evaluation of the functions of the dressing in regulating immune cells and promoting wound closure at the tissue, cellular and molecular levels; and 3) evaluation of the repaired skin against harmful stimulations. Skin wounds constitute a major public health problem, affecting more than 7.7 million people in the U.S. every year. The success of this project will open a new avenue of developing wound dressings, improve the quality of the lives of patients and reduce the heavy socioeconomic burden of skin wounds.